title: The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.
abstract: Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the "atopic march." Signaling between epithelial cells and innate immune cells via the cytokine thymic stromal lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here, we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Wilson
authors.forename: Lydia
authors.initials: L
authors.lastname: Thé
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Batia
authors.forename: Katherine
authors.initials: K
authors.lastname: Beattie
authors.forename: George E
authors.initials: GE
authors.lastname: Katibah
authors.forename: Shannan P
authors.initials: SP
authors.lastname: McClain
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Estandian
authors.forename: Diana M
authors.initials: DM
authors.lastname: Bautista
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003876:Dermatitis, Atopic / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D011537:Pruritus / Q000276:immunology; D018121:Receptors, Cytokine / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D018121:Receptors, Cytokine; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C410591:Tslpr protein, mouse; D002118:Calcium; D000094632:Thymic Stromal Lymphopoietin